title: Therapeutic targeting of SPINK1-positive prostate cancer.
abstract: Gene fusions involving ETS (erythroblastosis virus E26 transformation-specific) family transcription factors are found in ~50% of prostate cancers and as such can be used as a basis for the molecular subclassification of prostate cancer. Previously, we showed that marked overexpression of SPINK1 (serine peptidase inhibitor, Kazal type 1), which encodes a secreted serine protease inhibitor, defines an aggressive molecular subtype of ETS fusion-negative prostate cancers (SPINK1+/ETS⁻, ~10% of all prostate cancers). Here, we examined the potential of SPINK1 as an extracellular therapeutic target in prostate cancer. Recombinant SPINK1 protein (rSPINK1) stimulated cell proliferation in benign RWPE as well as cancerous prostate cells. Indeed, RWPE cells treated with either rSPINK1 or conditioned medium from 22RV1 prostate cancer cells (SPINK1+/ETS⁻) significantly increased cell invasion and intravasation when compared with untreated cells. In contrast, knockdown of SPINK1 in 22RV1 cells inhibited cell proliferation, cell invasion, and tumor growth in xenograft assays. 22RV1 cell proliferation, invasion, and intravasation were attenuated by a monoclonal antibody (mAb) to SPINK1 as well. We also demonstrated that SPINK1 partially mediated its neoplastic effects through interaction with the epidermal growth factor receptor (EGFR). Administration of antibodies to SPINK1 or EGFR (cetuximab) in mice bearing 22RV1 xenografts attenuated tumor growth by more than 60 and 40%, respectively, or ~75% when combined, without affecting PC3 xenograft (SPINK1⁻/ETS⁻) growth. Thus, this study suggests that SPINK1 may be a therapeutic target in a subset of patients with SPINK1+/ETS⁻ prostate cancer. Our results provide a rationale for both the development of humanized mAbs to SPINK1 and evaluation of EGFR inhibition in SPINK1+/ETS⁻ prostate cancers.
authors.affiliation: Michigan Center for Translational Pathology, Ann Arbor, MI 48109, USA.
authors.forename: Bushra
authors.initials: B
authors.lastname: Ateeq
authors.forename: Scott A
authors.initials: SA
authors.lastname: Tomlins
authors.forename: Bharathi
authors.initials: B
authors.lastname: Laxman
authors.forename: Irfan A
authors.initials: IA
authors.lastname: Asangani
authors.forename: Qi
authors.initials: Q
authors.lastname: Cao
authors.forename: Xuhong
authors.initials: X
authors.lastname: Cao
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Xiaoju
authors.initials: X
authors.lastname: Wang
authors.forename: Felix Y
authors.initials: FY
authors.lastname: Feng
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Pienta
authors.forename: Sooryanarayana
authors.initials: S
authors.lastname: Varambally
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D019898:Autocrine Communication; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000378:metabolism; D018390:Gene Targeting; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous; D014359:Trypsin Inhibitor, Kazal Pancreatic
chemical_list: D000911:Antibodies, Monoclonal; D002352:Carrier Proteins; D011993:Recombinant Fusion Proteins; C486642:SPINK1 protein, human; D014359:Trypsin Inhibitor, Kazal Pancreatic; D066246:ErbB Receptors